KR101600634B1 - Antitumor agent - Google Patents
Antitumor agent Download PDFInfo
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- KR101600634B1 KR101600634B1 KR1020107016835A KR20107016835A KR101600634B1 KR 101600634 B1 KR101600634 B1 KR 101600634B1 KR 1020107016835 A KR1020107016835 A KR 1020107016835A KR 20107016835 A KR20107016835 A KR 20107016835A KR 101600634 B1 KR101600634 B1 KR 101600634B1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
- A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D495/14—Ortho-condensed systems
Abstract
본 발명은, 아세틸화 히스톤과 브로모도메인 함유 단백질의 결합을 저해하는 화합물, 바람직하게는 이하의 일반식 (I)로 표시되는 티에노트리아졸로디아제핀 화합물 또는 그 의약상 허용할 수 있는 염 또는 이들의 수화물 또는 용매화물을 유효 성분으로서 이용하는 신규 항암제에 관한 것이다:
식 중, 각 기호는 명세서 중의 정의와 동의이다.The present invention relates to a compound inhibiting the binding of an acetylated histone and a bromo-domain-containing protein, preferably a thienotriazololadiazepine compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof or And a novel anticancer agent using the hydrate or solvate thereof as an active ingredient:
Wherein each symbol is as defined and synonymous in the specification.
Description
본 발명은, 아세틸화 히스톤과 브로모도메인 함유 단백질의 결합을 저해하는 화합물을 유효 성분으로 하는 항암제, 보다 구체적으로는 티에노트리아졸로디아제핀 화합물을 유효 성분으로 하는 항암제에 관한 것이다. The present invention relates to an anticancer agent comprising, as an active ingredient, a compound inhibiting the binding of an acetylated histone and a bromo-domain-containing protein, more specifically, to an anticancer agent comprising a thienotriazololadiazepine compound as an active ingredient.
히스톤(histone)은, 사람을 비롯한 다세포 생물부터 진균류(곰팡이·효모)로 대표되는 단세포 생물에 이르기까지, 진핵세포의 핵내에 공통으로 존재하고, 게놈 DNA와 이온 결합하는 염기성 단백질이다. 히스톤은 통상 5종류의 성분(H1, H2A, H2B, H3 및 H4)으로 이루어져 있고, 생물종을 초월하여 고도로 유사하다. 예컨대 히스톤 H4의 경우, 출아효모 히스톤 H4(전체 길이 102 아미노산 배열)와 사람 히스톤 H4(전체 길이 102 아미노산 배열)에서는 92%의 아미노산 배열이 일치하고, 상위는 겨우 8잔기이다. 1 생물중에 수만 종류 존재하는 것으로 상정되고 있는 천연 단백질 중에서, 히스톤은 진핵생물종간에서 가장 고도로 보존된 단백질인 것이 알려져 있다. 게놈 DNA는 이 히스톤과의 규칙적인 결합에 의해 포개져 있고, 양자의 복합체는 뉴클레오솜이라는 기본적인 구조 단위를 형성한다. 그리고, 이 뉴클레오솜이 응집하는 것에 의해 염색체의 크로마틴 구조가 형성되어 있다. 히스톤은 히스톤테일이라고 불리는 N 말단 부분에서, 아세틸화, 메틸화, 인산화, 유비퀴틴화, 및 SUMO화 등의 수식을 받고, 크로마틴 구조를 유지 또는 특이적으로 구조 변환하는 것에 의해 유전자 발현, DNA 복제, DNA 수복 등의 염색체 DNA상에서 생기는 반응이 컨트롤되어 있다. 히스톤의 번역 후 수식은 후성적인 조절 메커니즘이고, 진핵세포의 유전자 조절에 대하여 필수로 생각되고 있다. 예컨대 히스톤의 아세틸화는 한 쌍의 수식 효소(즉 히스톤 아세틸화 효소와 탈아세틸화 효소)에 의해 컨트롤되어 있다. 통상은 탈아세틸화 효소가 우위로 작용하고, 히스톤은 탈아세틸화 상태로 유지되고 있지만, 세포가 자극을 받아 활성화되면 히스톤 아세틸화 효소에 의해 히스톤의 리신 잔기의 아미노기가 아세틸화되고, 아미노기의 플러스 전하가 중화되는 것에 의해 뉴클레오솜간의 상호 작용이 느슨해져, 전사 인자가 리쿠르트되어 전사가 시작된다. Histone is a basic protein that exists in the nucleus of eukaryotic cells and ionically binds to genomic DNA, ranging from multicellular organisms such as humans to single celled organisms represented by fungi (fungi and yeast). Histones are usually composed of five components (H1, H2A, H2B, H3 and H4) and are highly similar, exceeding species. For example, in the case of histone H4, an amino acid sequence of 92% is identical in the emergence yeast histone H4 (102 amino acid sequence in total length) and human histone H4 (102 amino acid sequence in the full length). Of the natural proteins that are supposed to exist in tens of thousands of living things, histones are known to be the most highly conserved proteins among eukaryotic species. Genomic DNA is superimposed by regular bonds with this histone, and the complex of both forms a basic structural unit called a nucleosome. The chromosome structure of the chromosome is formed by aggregation of this nucleosome. The histone is subjected to an expression such as acetylation, methylation, phosphorylation, ubiquitination, and sumoylation at the N-terminal portion called histone tail, and the gene expression, DNA replication, The reaction on chromosomal DNA, such as DNA repair, is controlled. Post-translational modification of histones is a post-sexual regulatory mechanism and is considered essential for gene regulation of eukaryotic cells. For example, the acetylation of histone is controlled by a pair of modifying enzymes (i.e., histone acetylating enzymes and deacetylating enzymes). Usually, the deacetylase functions predominantly and the histone is maintained in the deacetylated state. However, when the cell is stimulated and activated, the amino group of the lysine residue of the histone is acetylated by the histone acetylating enzyme, As the charge is neutralized, the interaction between the nucleosomes is loosened and the transcription factor is recruited and transcription begins.
한편, 히스톤의 아세틸화 리신에 결합하는 단백질의 도메인 구조로서 브로모도메인이 알려져 있다. 사람에서는 30여 종류의 브로모도메인 함유 단백질이 존재한다. 이 중에서, 아세틸화 히스톤 H3/H4와 상호 작용하는 단백질에 BRD2, BRD3, BRD4가 있다. 이들 중에서, BRD4는 세포 주기나 유전자 발현에 관여하는 단백질인 것이 알려져 있다.(비특허문헌 1: Nature 399, 491-496, 1999)(비특허문헌 2: JOURNAL OF BIOLOGICAL CHEMISTRY Vol.282 No.18 13141-13145, 2007). 이 BRD4는 분자 내에 2개의 bromodomain과 하나의 extraterminal domain을 갖는 BET(bromodomain and extraterminal) 패밀리 단백질에 속한다. BRD4 이외의 BET 패밀리 단백질로서는, 사람 유래로는 BRD2, BRD3, BRD4가 알려져 있다. 지금까지, 이들 BET 패밀리 단백질과 아세틸화 히스톤과의 결합을 저해하는 화합물은 알려져 있지 않다. On the other hand, a bromo domain is known as a domain structure of a protein that binds to the acetylated lysine of histone. There are about 30 kinds of bromo domain-containing proteins in humans. Among these, BRD2, BRD3, and BRD4 are proteins that interact with the acetylated histone H3 / H4. Among these, BRD4 is known to be a protein involved in cell cycle and gene expression (Non-Patent Document 1: Nature 399, 491-496, 1999) (Non-Patent Document 2: JOURNAL OF BIOLOGICAL CHEMISTRY Vol. 282 No. 18 13141-13145, 2007). This BRD4 belongs to the BET (bromodomain and extraterminal) family of proteins with two bromodomains and one extraterminal domain in the molecule. As BET family proteins other than BRD4, BRD2, BRD3 and BRD4 are known from human. To date, no compound has been known to inhibit the binding of these BET family proteins to acetylated histones.
히스톤의 아세틸화에 관련하여, 히스톤 탈아세틸화 효소를 저해하는 화합물이 종양 세포의 세포 주기 정지, 분화 유도나 아포토시스 유도 활성을 나타내는 것이 알려져 있다(비특허문헌 3: Exp.Cell Res., 177, 122-131, 1988, 비특허문헌 4: Cancer Res.,47, 3688-3691, 1987). 그러나, 아세틸화 히스톤과 브로모도메인 함유 단백질의 결합을 저해하는 화합물이 종양 세포에 영향을 미치는지의 여부에 대해서는, 지금까지 전혀 보고가 없다. In relation to acetylation of histone, it has been known that a compound inhibiting histone deacetylase exhibits cell cycle arrest, induction of differentiation or apoptosis induction activity of tumor cells (Non-Patent Document 3: Exp. Cell Res., 177, 122-131, 1988, Non-Patent Document 4: Cancer Res., 47, 3688-3691, 1987). However, there has been no report on whether compounds that inhibit the binding of acetylated histone and the bromo domain-containing protein to the tumor cells have been affected.
최근, 흉선, 기도, 폐 등의 체내 상부 조직에서의 상피성 세포암(midline carcinoma)에 BRD4-NUT 융합 단백질이 발현되는 예가 있고, 이 융합 단백질의 발현이 확인되는 환자는 방사선 치료와 화학 요법에 저항성을 나타내어 환자의 예후가 좋지 않은 것이 알려져 있다(비특허문헌 6: Cancer Research vol.63 January 15 2003 p304-307, 비특허문헌 7: Journal of clinical oncology Vol. 22 No. 20 October 15 2004 p4135-4139). 또한 midline carcinoma에서 제9번 염색체와 제15번 염색체와의 t(9;15) 염색체 전좌에 의해 BRD3 단백질과 NUT 단백질과의 융합 단백질 BRD3-NUT도 형성되는 것이 보고되어 있다. BRD3-NUT 융합 단백질, BRD4-NUT 융합 단백질을 각각 발현하고 있는 환자 유래의 암세포주에 있어서, 그 융합 단백질의 발현을 siRNA에 의해 유전학적으로 저해하면, 그 암세포의 증식은 정지하는 것이 보고되어 있다(비특허문헌 8: Oncogene advance online publication 15 October 2007; doi: 10.1038/sj.onc.1210852). 따라서, 이들 융합 단백질의 기능을 저해하는 약제는 항암제로서 기대되지만, 아세틸화 히스톤과 융합 단백질상에 존재하는 브로모도메인과의 결합을 저해함으로써, 이들 융합 단백질의 기능이 저해된다는 보고는 없다. In recent years, BRD4-NUT fusion proteins have been expressed in epithelial cell carcinoma in the upper tissues of the thymus, airways, and lungs, and patients with confirmed expression of this fusion protein have been treated with radiation therapy and chemotherapy (See Non-Patent Document 6: Cancer Research vol.63 January 15 2003 p304-307, Non-Patent Document 7: Journal of Clinical Oncology Vol. 22 No. 20 October 15 2004 p4135- 4139). It has also been reported that the BRD3-NUT fusion protein between the BRD3 protein and the NUT protein is also formed by chromosome translocation of t (9; 15) between chromosome 9 and chromosome 15 in midline carcinoma. It has been reported that when the expression of the fusion protein is genetically inhibited by siRNA in a cancer cell line derived from a patient expressing each of BRD3-NUT fusion protein and BRD4-NUT fusion protein, the proliferation of the cancer cell is stopped (Non-Patent Document 8: Oncogene advance online publication 15 October 2007; doi: 10.1038 / sj.onc.1210852). Therefore, although agents that inhibit the function of these fusion proteins are expected as anticancer agents, there is no report that the function of these fusion proteins is inhibited by inhibiting the binding of the acetylated histone to the bromo domain present on the fusion protein.
한편, 하기 일반식 (I)On the other hand, the following general formula (I)
[식 중, [Wherein,
R1은 탄소수 1∼4의 알킬,R 1 is alkyl having 1 to 4 carbon atoms,
R2은 수소 원자; 할로겐 원자; 또는 할로겐 원자 또는 수산기로 치환되어 있어도 좋은 탄소수 1∼4의 알킬, R 2 is a hydrogen atom; A halogen atom; Or an alkyl having 1 to 4 carbon atoms which may be substituted with a halogen atom or a hydroxyl group,
R3은 할로겐 원자; 할로겐 원자, 탄소수 1∼4의 알킬, 탄소수 1∼4의 알콕시 또는 시아노로 치환되어 있어도 좋은 페닐; -NR5-(CH2)m-R6(여기서 R5은 수소 원자 또는 탄소수 1∼4의 알킬, m은 0∼4의 정수, R6은 할로겐 원자로 치환되어 있어도 좋은 페닐 또는 피리딜); 또는 -NR7-CO-(CH2)n-R8(여기서 R7은 수소 원자 또는 탄소수 1∼4의 알킬, n은 0∼2의 정수, R8은 할로겐 원자로 치환되어 있어도 좋은 페닐 또는 피리딜)R 3 is a halogen atom; A halogen atom, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, or phenyl optionally substituted with cyano; -NR 5 - (CH 2 ) m -R 6 (wherein R 5 is a hydrogen atom or alkyl having 1 to 4 carbon atoms, m is an integer of 0 to 4, and R 6 is phenyl or pyridyl optionally substituted with a halogen atom); Or -NR 7 -CO- (CH 2 ) n -R 8 wherein R 7 is a hydrogen atom or an alkyl having 1 to 4 carbon atoms, n is an integer of 0 to 2, R 8 is phenyl or pyridyl optionally substituted with a halogen atom Dill)
R4은 -(CH2)a-CO-NH-R9(여기서 a는 1∼4의 정수, R9는 탄소수 1∼4의 알킬; 탄소수 1∼4의 히드록시알킬; 탄소수 1∼4의 알콕시; 또는 탄소수 1∼4의 알킬, 탄소수 1∼4의 알콕시, 아미노 또는 수산기로 치환되어 있어도 좋은 페닐 또는 피리딜) 또는 -(CH2)b-COOR10(여기서 b는 1∼4의 정수, R10은 탄소수 1∼4의 알킬)을 나타냄]R 4 is - (CH 2 ) a -CO-NH-R 9 (wherein a is an integer of 1 to 4, R 9 is alkyl having 1 to 4 carbon atoms, hydroxyalkyl having 1 to 4 carbon atoms, (CH 2 ) b -COOR 10 (wherein b is an integer of 1 to 4, preferably 1 to 4, more preferably 1 to 4, And R < 10 > represents alkyl having 1 to 4 carbon atoms)
로 표시되는 티에노트리아졸로디아제핀 화합물은, 세포 접착 저해 작용을 가지며, 염증 성장 질환에 유용한 것, 또는 T 세포 상의 CD28로부터의 공자극 시그널을 저해하는 작용을 가지며, 이식시에서의 거절 반응, 자기 면역 질환, 알레르기성 질환에 유용한 것이 알려져 있다(특허문헌 1: 국제 공개 팜플렛 WO98/11111호, 특허문헌 2: 국제 공개 팜플렛 WO2006/129623호). 그러나, 이들 화합물이 아세틸화 히스톤과 BET 패밀리 단백질의 결합을 저해하는 작용을 갖는 것, 및 항암 작용을 갖는 것에 대해서는 일절 알려져 있지 않다., Has a cell adhesion inhibiting action and is useful for inflammatory growth diseases or has an action of inhibiting a co-stimulation signal from CD28 on T cells, and is useful as a rejection reaction at the time of transplantation, Autoimmune diseases and allergic diseases (Patent Document 1: International Publication Pamphlet WO98 / 11111, Patent Document 2: International Publication Pamphlet WO2006 / 129623). However, none of these compounds has an action of inhibiting the binding of the acetylated histone and the BET family protein and has an anticancer effect.
[특허문헌][Patent Literature]
특허문헌 1: 국제 공개 팜플렛 WO98/11111호Patent Document 1: International Publication Pamphlet WO98 / 11111
특허문헌 2: 국제 공개 팜플렛 WO2006/129623호 Patent Document 2: International Publication Pamphlet WO2006 / 129623
[비특허문헌][Non-Patent Document]
비특허문헌 1: Nature 399, p491-496, 1999Non-Patent Document 1: Nature 399, p491-496, 1999
비특허문헌 2: JOURNAL OF BIOLOGICAL CHEMISTRY Vol.282 No.18 p13141-13145, 2007Non-Patent Document 2: JOURNAL OF BIOLOGICAL CHEMISTRY Vol.282 No.18 p13141-13145, 2007
비특허문헌 3: Exp.Cell Res., 177, p122-131, 1988Non-Patent Document 3: Exp. Cell Res., 177, p122-131, 1988
비특허문헌 4: Cancer Res., 47, p3688-3691, 1987Non-Patent Document 4: Cancer Res., 47, p3688-3691, 1987
비특허문헌 5: American Journal of Pathology Vol. 159 No. 6, p1987-1992 December 2001Non-Patent Document 5: American Journal of Pathology Vol. 159 No. 6, p1987-1992 December 2001
비특허문헌 6: Cancer Research vol.63, p304-307 January 15 2003Non-Patent Document 6: Cancer Research vol.63, p304-307 January 15 2003
비특허문헌 7: Journal of clinical oncology Vol. 22 No. 20, p4135-4139 October 15 2004Non-Patent Document 7: Journal of clinical oncology Vol. 22 No. 20, p4135-4139 October 15 2004
비특허문헌 8: Oncogene advance online publication 15 October 2007; doi: 10.1038/sj.onc.1210852Non-Patent Document 8: Oncogene advance online publication 15 October 2007; doi: 10.1038 / sj.onc.1210852
본 발명의 과제는 신규 항암제를 제공하는 것에 있다. It is an object of the present invention to provide a novel anticancer agent.
본 발명자 등은 상기한 과제를 해결하기 위해 예의 노력한 결과, 아세틸화 히스톤과 브로모도메인 함유 단백질의 결합을 저해하는 화합물, 바람직하게는 이하의 일반식 (I)로 표시되는 티에노트리아졸로디아제핀 화합물 또는 그 의약상 허용할 수 있는 염 또는 이들의 수화물 또는 용매화물을 유효 성분으로서 이용함으로써, 신규한 항암제를 제공할 수 있는 것을 발견하여, 본 발명을 완성하기에 이르렀다. As a result of intensive efforts to solve the above problems, the present inventors have found that a compound inhibiting the binding of an acetylated histone and a bromo domain-containing protein, preferably a thienothiazololadia zein represented by the following general formula (I) A compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient, a novel anticancer agent can be provided, and the present invention has been accomplished.
즉, 본 발명의 요지는 이하와 같다. That is, the gist of the present invention is as follows.
1. 아세틸화 히스톤과 브로모도메인 함유 단백질의 결합을 저해하는 화합물 또는 그 의약상 허용할 수 있는 염 또는 이들의 수화물 또는 용매화물을 유효 성분으로 하는 항암제. 1. An anticancer agent comprising, as an active ingredient, a compound which inhibits the binding of an acetylated histone and a bromo-domain-containing protein, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.
2. 아세틸화 히스톤이 아세틸화 히스톤 H3 또는 아세틸화 히스톤 H4인 것인 1에 기재된 항암제. 2. The anticancer agent according to 1, wherein the acetylated histone is acetylated histone H3 or acetylated histone H4.
3. 아세틸화 히스톤이 아세틸화 히스톤 H4인 것인 1 또는 2에 기재된 항암제. 3. The anticancer agent according to 1 or 2, wherein the acetylated histone is acetylated histone H4.
4. 브로모도메인 함유 단백질이 BET 패밀리 단백질인 것인 1∼3 중 어느 한 항에 기재된 항암제. 4. The anticancer agent according to any one of items 1 to 3, wherein the Bromo domain-containing protein is a BET family protein.
5. BET 패밀리 단백질이 BRD2, BRD3, BRD4 또는 BRDt인 것인 4에 기재된 항암제. 5. The anticancer agent according to 4, wherein the BET family protein is BRD2, BRD3, BRD4 or BRDt.
6. BET 패밀리 단백질이 BRD2, BRD3 또는 BRD4인 것인 4 또는 5에 기재된 항암제. 6. The anticancer agent according to 4 or 5, wherein the BET family protein is BRD2, BRD3 or BRD4.
7. 아세틸화 히스톤과 브로모도메인 함유 단백질의 결합을 저해하는 화합물이 하기 일반식 (I)로 표시되는 티에노트리아졸로디아제핀 화합물 또는 그 의약상 허용할 수 있는 염 또는 이들의 수화물 또는 용매화물인 것인 1∼6 중 어느 하나에 기재된 항암제: 7. A method of inhibiting the binding of an acetylated histone and a bromo-domain-containing protein to a thienothiazolazolidinazine compound represented by the following formula (I), a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof The anticancer agent according to any one of 1 to 6,
식 중, Wherein,
R1은 탄소수 1∼4의 알킬, R 1 is alkyl having 1 to 4 carbon atoms,
R2은 수소 원자; 할로겐 원자; 또는 할로겐 원자 또는 수산기로 치환되어 있어도 좋은 탄소수 1∼4의 알킬, R 2 is a hydrogen atom; A halogen atom; Or an alkyl having 1 to 4 carbon atoms which may be substituted with a halogen atom or a hydroxyl group,
R3은 할로겐 원자; 할로겐 원자, 탄소수 1∼4의 알킬, 탄소수 1∼4의 알콕시 또는 시아노로 치환되어 있어도 좋은 페닐; -NR5-(CH2)m-R6(여기서, R5은 수소 원자 또는 탄소수 1∼4의 알킬, m은 0∼4의 정수, R6은 할로겐 원자로 치환되어 있어도 좋은 페닐 또는 피리딜); 또는 -NR7-CO-(CH2)n-R8(여기서 R7은 수소 원자 또는 탄소수 1∼4의 알킬, n은 0∼2의 정수, R8은 할로겐 원자로 치환되어 있어도 좋은 페닐 또는 피리딜), R 3 is a halogen atom; A halogen atom, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, or phenyl optionally substituted with cyano; (Wherein R 5 is a hydrogen atom or alkyl having 1 to 4 carbon atoms, m is an integer of 0 to 4, and R 6 is phenyl or pyridyl which may be substituted with a halogen atom), -NR 5 - (CH 2 ) m -R 6 ; Or -NR 7 -CO- (CH 2 ) n -R 8 wherein R 7 is a hydrogen atom or an alkyl having 1 to 4 carbon atoms, n is an integer of 0 to 2, R 8 is phenyl or pyridyl optionally substituted with a halogen atom Dill),
R4는 -(CH2)a-CO-NH-R9(여기서 a는 1∼4의 정수, R9는 탄소수 1∼4의 알킬; 탄소수 1∼4의 히드록시알킬; 탄소수 1∼4의 알콕시; 또는 탄소수 1∼4의 알킬, 탄소수 1∼4의 알콕시, 아미노 또는 수산기로 치환되어 있어도 좋은 페닐 또는 피리딜) 또는 -(CH2)b-COOR10(여기서 b는 1∼4의 정수, R10은 탄소수 1∼4의 알킬)을 나타낸다.R 4 is - (CH 2 ) a -CO-NH-R 9 (wherein a is an integer of 1 to 4, R 9 is alkyl having 1 to 4 carbon atoms, hydroxyalkyl having 1 to 4 carbon atoms, (CH 2 ) b -COOR 10 (wherein b is an integer of 1 to 4, preferably 1 to 4, more preferably 1 to 4, And R < 10 > represents alkyl having 1 to 4 carbon atoms).
8. 일반식 (I)중 치환기 R4가 결합되어 있는 비대칭 탄소 원자의 입체 배치가 S배치인 것인 7에 기재된 항암제. 8. The anticancer agent according to 7, wherein the configuration of the asymmetric carbon atom to which the substituent R 4 is bonded in the general formula (I) is S-configuration.
9. 일반식 (I)중, R1이 메틸인 것인 7 또는 8에 기재된 항암제. 9. The anticancer agent according to 7 or 8, wherein, in the general formula (I), R 1 is methyl.
10. 일반식 (I)중, R2가 메틸인 것인 7∼9 중 어느 하나에 기재된 항암제. 10. The anticancer agent according to any one of 7 to 9, wherein in the general formula (I), R 2 is methyl.
11. 일반식 (I)중, R3이 염소 원자, 시아노페닐, 페닐아미노, 페네틸카르보닐아미노인 것인 7∼10 중 어느 하나에 기재된 항암제. 11. The anticancer agent according to any one of 7 to 10, wherein in the general formula (I), R 3 is a chlorine atom, cyanophenyl, phenylamino or phenethylcarbonylamino.
12. 일반식 (I)중, R4가 히드록시페닐아미노카르보닐메틸, 메톡시카르보닐메틸인 것인 7∼11 중 어느 하나에 기재된 항암제. 12. The anticancer agent according to any one of 7 to 11, wherein in the general formula (I), R 4 is hydroxyphenylaminocarbonylmethyl or methoxycarbonylmethyl.
13. 일반식 (I)로 표시되는 화합물이 (S)-2-[4-(4-클로로페닐)-2,3,9-트리메틸-6H-티에노[3,2-f][1,2,4]트리아졸로[4,3-a][1,4]디아제핀-6-일〕-N-(4-히드록시페닐)아세트아미도 또는 그 2수화물, 13. The compound of formula (I) is (S) -2- [4- (4-chlorophenyl) -2,3,9- 2,4] triazolo [4,3-a] [1,4] diazepin-6-yl] -N- (4-hydroxyphenyl) acetamido or its dihydrate,
메틸(S)-{4-(3'-시아노비페닐-4-일)-2,3,9-트리메틸-6H-티에노[3,2-f][1,2,4]트리아졸로[4,3-a][1,4]디아제핀-6-일}아세테이트, Methyl (S) - {4- (3'-cyanobiphenyl-4-yl) -2,3,9-trimethyl-6H- thieno [3,2- f] [1,2,4] triazolo [ 4,3-a] [1,4] diazepin-6-yl} acetate,
메틸(S)-{2,3,9-트리메틸-4-(4-페닐아미노페닐)-6H-티에노[3,2-f][1,2,4]트리아졸로[4,3-a][1,4]디아제핀-6-일}아세테이트 또는Methyl (S) - {2,3,9-trimethyl-4- (4-phenylaminophenyl) -6H-thieno [3,2- f] [1,2,4] triazolo [ ] [L, 4] diazepin-6-yl} acetate or
메틸(S)-{2,3,9-트리메틸-4-[4-(3-페닐프로피오닐아미노)페닐]-6H-티에노[3,2-f][1,2,4]트리아졸로[4,3-a][1,4]디아제핀-6-일}아세테이트인 것인 7∼12 중 어느 하나에 기재된 항암제. Methyl (S) - {2,3,9-trimethyl-4- [4- (3- phenylpropionylamino) phenyl] -6H- thieno [3,2- f] [1,2,4] [4,3-a] [1,4] diazepin-6-yl} acetate.
14. 암이 혈액암, 골수종, 간암, 난소암, 전립선암, 폐암, 골육종 또는 대장암인 것인 1∼13 중 어느 하나에 기재된 항암제. 14. The anticancer agent according to any one of 1 to 13, wherein the cancer is blood cancer, myeloma, liver cancer, ovarian cancer, prostate cancer, lung cancer, osteosarcoma or colon cancer.
15. (S)-2-[4-(4-클로로페닐)-2,3,9-트리메틸-6H-티에노[3,2-f][1,2,4]트리아졸로[4,3-a][1,4]디아제핀-6-일]-N-(4-히드록시페닐)아세트아미드 또는 그 2수화물을 유효 성분으로 하는 항폐암제. 15. (S) -2- [4- (4-chlorophenyl) -2,3,9-trimethyl-6H-thieno [3,2- f] [1,2,4] triazolo [ -a] [1,4] diazepin-6-yl] -N- (4-hydroxyphenyl) acetamide or a dihydrate thereof as an active ingredient.
16. 하기 일반식 (I)로 표시되는 티에노트리아졸로디아제핀 화합물 또는 그 의약상 허용할 수 있는 염 또는 이들의 수화물 또는 용매화물을 유효 성분으로 하는 항암제:16. An anticancer agent comprising, as an active ingredient, a thienotriazololodiazepine compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof:
식 중, Wherein,
R1은 탄소수 1∼4의 알킬, R 1 is alkyl having 1 to 4 carbon atoms,
R2은 수소 원자; 할로겐 원자; 또는 할로겐 원자 또는 수산기로 치환되어 있어도 좋은 탄소수 1∼4의 알킬, R 2 is a hydrogen atom; A halogen atom; Or an alkyl having 1 to 4 carbon atoms which may be substituted with a halogen atom or a hydroxyl group,
R3은 할로겐 원자; 할로겐 원자, 탄소수 1∼4의 알킬, 탄소수 1∼4의 알콕시 또는 시아노로 치환되어 있어도 좋은 페닐; -NR5-(CH2)m-R6(여기서, R5은 수소 원자 또는 탄소수 1∼4의 알킬, m은 0∼4의 정수, R6은 할로겐 원자로 치환되어 있어도 좋은 페닐 또는 피리딜); 또는 -NR7-CO-(CH2)n-R8(여기서 R7은 수소 원자 또는 탄소수 1∼4의 알킬, n은 0∼2의 정수, R8은 할로겐 원자로 치환되어 있어도 좋은 페닐 또는 피리딜), R 3 is a halogen atom; A halogen atom, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, or phenyl optionally substituted with cyano; (Wherein R 5 is a hydrogen atom or alkyl having 1 to 4 carbon atoms, m is an integer of 0 to 4, and R 6 is phenyl or pyridyl which may be substituted with a halogen atom), -NR 5 - (CH 2 ) m -R 6 ; Or -NR 7 -CO- (CH 2 ) n -R 8 wherein R 7 is a hydrogen atom or an alkyl having 1 to 4 carbon atoms, n is an integer of 0 to 2, R 8 is phenyl or pyridyl optionally substituted with a halogen atom Dill),
R4는 -(CH2)a-CO-NH-R9(여기서 a는 1∼4의 정수, R9는 탄소수 1∼4의 알킬; 탄소수 1∼4의 히드록시알킬; 탄소수 1∼4의 알콕시; 또는 탄소수 1∼4의 알킬, 탄소수 1∼4의 알콕시, 아미노 또는 수산기로 치환되어 있어도 좋은 페닐 또는 피리딜) 또는 -(CH2)b-COOR10(여기서 b는 1∼4의 정수, R10은 탄소수 1∼4의 알킬)을 나타낸다.R 4 is - (CH 2 ) a -CO-NH-R 9 (wherein a is an integer of 1 to 4, R 9 is alkyl having 1 to 4 carbon atoms, hydroxyalkyl having 1 to 4 carbon atoms, (CH 2 ) b -COOR 10 (wherein b is an integer of 1 to 4, preferably 1 to 4, more preferably 1 to 4, And R < 10 > represents alkyl having 1 to 4 carbon atoms).
17. 하기 일반식 (I)로 표시되는 티에노트리아졸로디아제핀 화합물 또는 그 의약상 허용할 수 있는 염 또는 이들의 수화물 또는 용매화물을 유효 성분으로 하는 아세틸화 히스톤과 브로모도메인 함유 단백질의 결합 저해제:17. A pharmaceutical composition comprising a combination of an acetylated histone and a bromo-domain-containing protein as an active ingredient, wherein the thienotriazolodiazepine compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof or a hydrate or solvate thereof, Inhibitors:
식 중, Wherein,
R1은 탄소수 1∼4의 알킬, R 1 is alkyl having 1 to 4 carbon atoms,
R2은 수소 원자; 할로겐 원자; 또는 할로겐 원자 또는 수산기로 치환되어 있어도 좋은 탄소수 1∼4의 알킬, R 2 is a hydrogen atom; A halogen atom; Or an alkyl having 1 to 4 carbon atoms which may be substituted with a halogen atom or a hydroxyl group,
R3은 할로겐 원자; 할로겐 원자, 탄소수 1∼4의 알킬, 탄소수 1∼4의 알콕시 또는 시아노로 치환되어 있어도 좋은 페닐; -NR5-(CH2)m-R6(여기서, R5은 수소 원자 또는 탄소수 1∼4의 알킬, m은 0∼4의 정수, R6은 할로겐 원자로 치환되어 있어도 좋은 페닐 또는 피리딜); 또는 -NR7-CO-(CH2)n-R8(여기서 R7은 수소 원자 또는 탄소수 1∼4의 알킬, n은 0∼2의 정수, R8은 할로겐 원자로 치환되어 있어도 좋은 페닐 또는 피리딜), R 3 is a halogen atom; A halogen atom, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, or phenyl optionally substituted with cyano; (Wherein R 5 is a hydrogen atom or alkyl having 1 to 4 carbon atoms, m is an integer of 0 to 4, and R 6 is phenyl or pyridyl which may be substituted with a halogen atom), -NR 5 - (CH 2 ) m -R 6 ; Or -NR 7 -CO- (CH 2 ) n -R 8 wherein R 7 is a hydrogen atom or an alkyl having 1 to 4 carbon atoms, n is an integer of 0 to 2, R 8 is phenyl or pyridyl optionally substituted with a halogen atom Dill),
R4는 -(CH2)a-CO-NH-R9(여기서 a는 1∼4의 정수, R9는 탄소수 1∼4의 알킬; 탄소수 1∼4의 히드록시알킬; 탄소수 1∼4의 알콕시; 또는 탄소수 1∼4의 알킬, 탄소수 1∼4의 알콕시, 아미노 또는 수산기로 치환되어 있어도 좋은 페닐 또는 피리딜) 또는 -(CH2)b-COOR10(여기서 b는 1∼4의 정수, R10은 탄소수 1∼4의 알킬)을 나타낸다. R 4 is - (CH 2 ) a -CO-NH-R 9 (wherein a is an integer of 1 to 4, R 9 is alkyl having 1 to 4 carbon atoms, hydroxyalkyl having 1 to 4 carbon atoms, (CH 2 ) b -COOR 10 (wherein b is an integer of 1 to 4, preferably 1 to 4, more preferably 1 to 4, And R < 10 > represents alkyl having 1 to 4 carbon atoms).
18. 포유동물에 대하여, 아세틸화 히스톤과 브로모도메인 함유 단백질의 결합을 저해하는 화합물 또는 그 의약상 허용할 수 있는 염 또는 이들의 수화물 또는 용매화물의 유효량을 투여하는 것을 특징으로 하는 암의 치료 방법. 18. A method for treating cancer which comprises administering to a mammal an effective amount of a compound inhibiting the binding of an acetylated histone and a bromo domain containing protein or a pharmaceutically acceptable salt thereof or a hydrate or solvate thereof Way.
19. 포유동물에 대하여, 아세틸화 히스톤과 브로모도메인 함유 단백질의 결합을 저해하는 하기 일반식 (I)로 표시되는 티에노트리아졸로디아제핀 화합물 또는 그 의약상 허용할 수 있는 염 또는 이들의 수화물 또는 용매화물의 유효량을 투여하는 것을 특징으로 하는 암의 치료 방법:19. A thienotriazololodiazepine compound represented by the following formula (I) for inhibiting the binding of an acetylated histone and a bromo domain-containing protein to mammals, or a pharmaceutically acceptable salt thereof or a hydrate thereof Or an effective amount of a solvate.
식 중, Wherein,
R1은 탄소수 1∼4의 알킬, R 1 is alkyl having 1 to 4 carbon atoms,
R2은 수소 원자; 할로겐 원자; 또는 할로겐 원자 또는 수산기로 치환되어 있어도 좋은 탄소수 1∼4의 알킬, R 2 is a hydrogen atom; A halogen atom; Or an alkyl having 1 to 4 carbon atoms which may be substituted with a halogen atom or a hydroxyl group,
R3은 할로겐 원자; 할로겐 원자, 탄소수 1∼4의 알킬, 탄소수 1∼4의 알콕시 또는 시아노로 치환되어 있어도 좋은 페닐; -NR5-(CH2)m-R6(여기서, R5은 수소 원자 또는 탄소수 1∼4의 알킬, m은 0∼4의 정수, R6은 할로겐 원자로 치환되어 있어도 좋은 페닐 또는 피리딜); 또는 -NR7-CO-(CH2)n-R8(여기서 R7은 수소 원자 또는 탄소수 1∼4의 알킬, n은 0∼2의 정수, R8은 할로겐 원자로 치환되어 있어도 좋은 페닐 또는 피리딜), R 3 is a halogen atom; A halogen atom, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, or phenyl optionally substituted with cyano; (Wherein R 5 is a hydrogen atom or alkyl having 1 to 4 carbon atoms, m is an integer of 0 to 4, and R 6 is phenyl or pyridyl which may be substituted with a halogen atom), -NR 5 - (CH 2 ) m -R 6 ; Or -NR 7 -CO- (CH 2 ) n -R 8 wherein R 7 is a hydrogen atom or an alkyl having 1 to 4 carbon atoms, n is an integer of 0 to 2, R 8 is phenyl or pyridyl optionally substituted with a halogen atom Dill),
R4는 -(CH2)a-CO-NH-R9(여기서 a는 1∼4의 정수, R9는 탄소수 1∼4의 알킬; 탄소수 1∼4의 히드록시알킬; 탄소수 1∼4의 알콕시; 또는 탄소수 1∼4의 알킬, 탄소수 1∼4의 알콕시, 아미노 또는 수산기로 치환되어 있어도 좋은 페닐 또는 피리딜) 또는 -(CH2)b-COOR10(여기서 b는 1∼4의 정수, R10은 탄소수 1∼4의 알킬)을 나타낸다.R 4 is - (CH 2 ) a -CO-NH-R 9 (wherein a is an integer of 1 to 4, R 9 is alkyl having 1 to 4 carbon atoms, hydroxyalkyl having 1 to 4 carbon atoms, (CH 2 ) b -COOR 10 (wherein b is an integer of 1 to 4, preferably 1 to 4, more preferably 1 to 4, And R < 10 > represents alkyl having 1 to 4 carbon atoms).
20. 암의 예방 또는 치료제를 제조하기 위한, 아세틸화 히스톤과 브로모도메인 함유 단백질의 결합을 저해하는 화합물 또는 그 의약상 허용할 수 있는 염 또는 이들의 수화물 또는 용매화물의 용도. 20. Use of a compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, for inhibiting the binding of an acetylated histone and a bromo domain-containing protein, for the manufacture of a preventive or therapeutic agent for cancer.
21. 암의 예방 또는 치료제를 제조하기 위한, 아세틸화 히스톤과 브로모도메인 함유 단백질의 결합을 저해하는 하기 일반식 (I)로 표시되는 티에노트리아졸로디아제핀 화합물 또는 그 의약상 허용할 수 있는 염 또는 이들의 수화물 또는 용매화물의 용도:21. A thienotriazololodiazepine compound represented by the following general formula (I) for inhibiting the binding of an acetylated histone and a bromo domain-containing protein for producing a preventive or therapeutic agent for cancer, Uses of salts or hydrates or solvates thereof:
식 중, Wherein,
R1은 탄소수 1∼4의 알킬, R 1 is alkyl having 1 to 4 carbon atoms,
R2은 수소 원자; 할로겐 원자; 또는 할로겐 원자 또는 수산기로 치환되어 있어도 좋은 탄소수 1∼4의 알킬, R 2 is a hydrogen atom; A halogen atom; Or an alkyl having 1 to 4 carbon atoms which may be substituted with a halogen atom or a hydroxyl group,
R3은 할로겐 원자; 할로겐 원자, 탄소수 1∼4의 알킬, 탄소수 1∼4의 알콕시 또는 시아노로 치환되어 있어도 좋은 페닐; -NR5-(CH2)m-R6(여기서, R5은 수소 원자 또는 탄소수 1∼4의 알킬, m은 0∼4의 정수, R6은 할로겐 원자로 치환되어 있어도 좋은 페닐 또는 피리딜); 또는 -NR7-CO-(CH2)n-R8(여기서 R7은 수소 원자 또는 탄소수 1∼4의 알킬, n은 0∼2의 정수, R8은 할로겐 원자로 치환되어 있어도 좋은 페닐 또는 피리딜), R 3 is a halogen atom; A halogen atom, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, or phenyl optionally substituted with cyano; (Wherein R 5 is a hydrogen atom or alkyl having 1 to 4 carbon atoms, m is an integer of 0 to 4, and R 6 is phenyl or pyridyl which may be substituted with a halogen atom), -NR 5 - (CH 2 ) m -R 6 ; Or -NR 7 -CO- (CH 2 ) n -R 8 wherein R 7 is a hydrogen atom or an alkyl having 1 to 4 carbon atoms, n is an integer of 0 to 2, R 8 is phenyl or pyridyl optionally substituted with a halogen atom Dill),
R4는 -(CH2)a-CO-NH-R9(여기서 a는 1∼4의 정수, R9는 탄소수 1∼4의 알킬; 탄소수 1∼4의 히드록시알킬; 탄소수 1∼4의 알콕시; 또는 탄소수 1∼4의 알킬, 탄소수 1∼4의 알콕시, 아미노 또는 수산기로 치환되어 있어도 좋은 페닐 또는 피리딜) 또는 -(CH2)b-COOR10(여기서 b는 1∼4의 정수, R10은 탄소수 1∼4의 알킬)을 나타낸다. R 4 is - (CH 2 ) a -CO-NH-R 9 (wherein a is an integer of 1 to 4, R 9 is alkyl having 1 to 4 carbon atoms, hydroxyalkyl having 1 to 4 carbon atoms, (CH 2 ) b -COOR 10 (wherein b is an integer of 1 to 4, preferably 1 to 4, more preferably 1 to 4, And R < 10 > represents alkyl having 1 to 4 carbon atoms).
22. 암의 예방 또는 치료 방법에 이용하는, 아세틸화 히스톤과 브로모도메인 함유 단백질의 결합을 저해하는 화합물 또는 그 의약상 허용할 수 있는 염 또는 이들의 수화물 또는 용매화물. 22. A compound for inhibiting the binding of an acetylated histone and a bromo-domain-containing protein, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, for use in a method of preventing or treating cancer.
23. 암의 예방 또는 치료 방법에 이용하는, 아세틸화 히스톤과 브로모도메인 함유 단백질의 결합을 저해하는 하기 일반식 (I)로 표시되는 티에노트리아졸로디아제핀 화합물 또는 그 의약상 허용할 수 있는 염 또는 이들의 수화물 또는 용매화물:23. A thienotriazololadiazepine compound represented by the following general formula (I) for inhibiting the binding of an acetylated histone and a bromo-domain-containing protein, which is used in a method of preventing or treating cancer, or a pharmaceutically acceptable salt thereof Or a hydrate or solvate thereof:
식 중, Wherein,
R1은 탄소수 1∼4의 알킬, R 1 is alkyl having 1 to 4 carbon atoms,
R2은 수소 원자; 할로겐 원자; 또는 할로겐 원자 또는 수산기로 치환되어 있어도 좋은 탄소수 1∼4의 알킬, R 2 is a hydrogen atom; A halogen atom; Or an alkyl having 1 to 4 carbon atoms which may be substituted with a halogen atom or a hydroxyl group,
R3은 할로겐 원자; 할로겐 원자, 탄소수 1∼4의 알킬, 탄소수 1∼4의 알콕시 또는 시아노로 치환되어 있어도 좋은 페닐; -NR5-(CH2)m-R6(여기서, R5은 수소 원자 또는 탄소수 1∼4의 알킬, m은 0∼4의 정수, R6은 할로겐 원자로 치환되어 있어도 좋은 페닐 또는 피리딜); 또는 -NR7-CO-(CH2)n-R8(여기서 R7은 수소 원자 또는 탄소수 1∼4의 알킬, n은 0∼2의 정수, R8은 할로겐 원자로 치환되어 있어도 좋은 페닐 또는 피리딜), R 3 is a halogen atom; A halogen atom, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, or phenyl optionally substituted with cyano; (Wherein R 5 is a hydrogen atom or alkyl having 1 to 4 carbon atoms, m is an integer of 0 to 4, and R 6 is phenyl or pyridyl which may be substituted with a halogen atom), -NR 5 - (CH 2 ) m -R 6 ; Or -NR 7 -CO- (CH 2 ) n -R 8 wherein R 7 is a hydrogen atom or an alkyl having 1 to 4 carbon atoms, n is an integer of 0 to 2, R 8 is phenyl or pyridyl optionally substituted with a halogen atom Dill),
R4는 -(CH2)a-CO-NH-R9(여기서 a는 1∼4의 정수, R9는 탄소수 1∼4의 알킬; 탄소수 1∼4의 히드록시알킬; 탄소수 1∼4의 알콕시; 또는 탄소수 1∼4의 알킬, 탄소수 1∼4의 알콕시, 아미노 또는 수산기로 치환되어 있어도 좋은 페닐 또는 피리딜) 또는 -(CH2)b-COOR10(여기서 b는 1∼4의 정수, R10은 탄소수 1∼4의 알킬)을 나타낸다. R 4 is - (CH 2 ) a -CO-NH-R 9 (wherein a is an integer of 1 to 4, R 9 is alkyl having 1 to 4 carbon atoms, hydroxyalkyl having 1 to 4 carbon atoms, (CH 2 ) b -COOR 10 (wherein b is an integer of 1 to 4, preferably 1 to 4, more preferably 1 to 4, And R < 10 > represents alkyl having 1 to 4 carbon atoms).
본 발명에 의하면, 신규 항암제를 제공할 수 있다. According to the present invention, a novel anticancer agent can be provided.
본 발명에 의해 제공되는 항암제는 유효 성분으로서 아세틸화 히스톤과 브로모도메인 함유 단백질의 결합을 저해하는 화합물을 함유하고 있다. 히스톤은 이미 진술한 바와 같이 5종류의 성분으로 이루어져 있지만, 본 발명에서는 H3 또는 H4가 아세틸화된 아세틸화 히스톤 H3 또는 아세틸화 히스톤 H4와 브로모도메인 함유 단백질의 결합을 저해하는 화합물을 유효 성분으로서 이용하는 것이 바람직하다. 브로모도메인 함유 단백질에 대해서는, BET 패밀리에 속하는 단백질인 것이 바람직하다. BET 패밀리 단백질은 사람 유래 이외에도, 파리 유래, 이스트균 유래의 단백질 등이 알려져 있지만 본 발명에서는 사람 유래의 BET 패밀리 단백질과 아세틸화 히스톤과의 결합을 저해하는 화합물을 유효 성분으로서 이용하는 것이 바람직하다. 사람 유래의 BET 패밀리 단백질의 구체예로서는, BRD2, BRD3, BRD4, BRDt를 들 수 있고, BRD2, BRD3 또는 BRD4를 바람직한 예로서 들 수 있다. 따라서, 본 발명에서 이용하는 유효 성분으로서 바람직한 화합물은, 아세틸화 히스톤 H3 또는 아세틸화 히스톤 H4(바람직하게는 아세틸화 히스톤 H4)와 BRD2, BRD3 또는 BRD4의 결합을 저해하는 화합물을 들 수 있다. The anticancer agent provided by the present invention contains, as an active ingredient, a compound which inhibits the binding of the acetylated histone and the bromo domain-containing protein. Although the histone is composed of five components as described above, in the present invention, a compound which inhibits the binding of the acetylated histone H3 acetylated with H3 or H4 to acetylated histone H4 or the acetylated histone H4 with the bromo domain- Is preferably used. As to the bromo domain-containing protein, it is preferable that the protein belongs to the BET family. In addition to human-derived BET family proteins, proteins derived from flies and yeasts are also known. In the present invention, it is preferable to use, as an active ingredient, a compound that inhibits binding of BET family proteins derived from humans to acetylated histones. Specific examples of human-derived BET family proteins include BRD2, BRD3, BRD4 and BRDt, and BRD2, BRD3 or BRD4 can be mentioned as preferred examples. Therefore, a preferable compound as an active ingredient used in the present invention is a compound which inhibits the binding of acetylated histone H3 or acetylated histone H4 (preferably acetylated histone H4) to BRD2, BRD3 or BRD4.
본 발명에서 유효 성분으로서 이용하는 화합물의 구체적인 구조를 들면, 일례로서 이하의 일반식 (I)로 표시되는 티에노트리아졸로디아제핀 화합물 또는 그 의약상 허용할 수 있는 염 또는 이들의 수화물 또는 용매화물을 들 수 있다:Examples of the specific structure of the compound used as the active ingredient in the present invention include thienotriazololodiazepine compounds represented by the following general formula (I), pharmaceutically acceptable salts thereof, hydrates or solvates thereof You can:
식 중, Wherein,
R1은 탄소수 1∼4의 알킬, R 1 is alkyl having 1 to 4 carbon atoms,
R2은 수소 원자; 할로겐 원자; 또는 할로겐 원자 또는 수산기로 치환되어 있어도 좋은 탄소수 1∼4의 알킬, R 2 is a hydrogen atom; A halogen atom; Or an alkyl having 1 to 4 carbon atoms which may be substituted with a halogen atom or a hydroxyl group,
R3은 할로겐 원자; 할로겐 원자, 탄소수 1∼4의 알킬, 탄소수 1∼4의 알콕시 또는 시아노로 치환되어 있어도 좋은 페닐; -NR5-(CH2)m-R6(여기서, R5은 수소 원자 또는 탄소수 1∼4의 알킬, m은 0∼4의 정수, R6은 할로겐 원자로 치환되어 있어도 좋은 페닐 또는 피리딜); 또는 -NR7-CO-(CH2)n-R8(여기서 R7은 수소 원자 또는 탄소수 1∼4의 알킬, n은 0∼2의 정수, R8은 할로겐 원자로 치환되어 있어도 좋은 페닐 또는 피리딜), R 3 is a halogen atom; A halogen atom, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, or phenyl optionally substituted with cyano; (Wherein R 5 is a hydrogen atom or alkyl having 1 to 4 carbon atoms, m is an integer of 0 to 4, and R 6 is phenyl or pyridyl which may be substituted with a halogen atom), -NR 5 - (CH 2 ) m -R 6 ; Or -NR 7 -CO- (CH 2 ) n -R 8 wherein R 7 is a hydrogen atom or an alkyl having 1 to 4 carbon atoms, n is an integer of 0 to 2, R 8 is phenyl or pyridyl optionally substituted with a halogen atom Dill),
R4는 -(CH2)a-CO-NH-R9(여기서 a는 1∼4의 정수, R9는 탄소수 1∼4의 알킬; 탄소수 1∼4의 히드록시알킬; 탄소수 1∼4의 알콕시; 또는 탄소수 1∼4의 알킬, 탄소수 1∼4의 알콕시, 아미노 또는 수산기로 치환되어 있어도 좋은 페닐 또는 피리딜) 또는 -(CH2)b-COOR10(여기서 b는 1∼4의 정수, R10은 탄소수 1∼4의 알킬)을 나타낸다.R 4 is - (CH 2 ) a -CO-NH-R 9 (wherein a is an integer of 1 to 4, R 9 is alkyl having 1 to 4 carbon atoms, hydroxyalkyl having 1 to 4 carbon atoms, (CH 2 ) b -COOR 10 (wherein b is an integer of 1 to 4, preferably 1 to 4, more preferably 1 to 4, And R < 10 > represents alkyl having 1 to 4 carbon atoms).
본 명세서에서, 탄소수 1∼4의 알킬이란, 직쇄 또는 분지쇄의 알킬을 의미하고, 예컨대 메틸, 에틸, n-프로필, 이소프로필, n-부틸, 이소부틸, t-부틸 등을 들 수 있다. In the present specification, the alkyl having 1 to 4 carbon atoms means straight chain or branched chain alkyl, and examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl.
할로겐 원자란, 불소 원자, 염소 원자, 브롬 원자, 요오드 원자를 의미한다. The halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
탄소수 1∼4의 알콕시란, 직쇄 또는 분지쇄의 알콕시를 의미하고, 예컨대 메톡시, 에톡시, n-프로폭시, 이소프로폭시, n-부톡시, 이소부톡시, t-부톡시 등을 들 수 있다. Alkoxy of 1 to 4 carbon atoms means straight or branched chain alkoxy and includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, have.
탄소수 1∼4의 히드록시알킬이란, 1∼9개의 수산기로 치환되어 있는 전술한 탄소수 1∼4의 알킬을 의미하고, 히드록시메틸, 히드록시에틸 등을 구체예로서 들 수 있다. The hydroxyalkyl having 1 to 4 carbon atoms means the above-mentioned alkyl having 1 to 4 carbon atoms which is substituted with 1 to 9 hydroxyl groups, and specific examples include hydroxymethyl, hydroxyethyl and the like.
R1의 바람직한 예로서는 메틸을 들 수 있다. A preferable example of R 1 is methyl.
R2의 바람직한 예로서는, 할로겐 원자, 메틸 및 히드록시메틸을 들 수 있고, 염소 원자, 메틸 및 히드록시메틸을 보다 바람직한 예로서 들 수 있다. 가장 바람직한 예로서는 메틸을 들 수 있다. Preferable examples of R 2 include a halogen atom, methyl and hydroxymethyl, and more preferred examples include a chlorine atom, methyl and hydroxymethyl. A most preferred example is methyl.
R3의 바람직한 예로서는, 할로겐 원자, 메톡시페닐, 시아노페닐, -NR5'-(CH2)m'-R6'(여기서 R5'은 수소 원자 또는 메틸, m'은 0 또는 1, R6'은 페닐, 피리딜 또는 불소 원자로 치환된 페닐) 및 -NR7'-CO-(CH2)n'-R8'(여기서 R7'은 수소 원자, n'은 2, R8'은 페닐)을 들 수 있고, 염소 원자, 시아노페닐, 페닐아미노 및 페네틸카르보닐아미노를 보다 바람직한 예로서 들 수 있다. 가장 바람직한 예로서는, 염소 원자 및 3-시아노페닐을 들 수 있다. Preferred examples of R 3 include a halogen atom, methoxyphenyl, cyanophenyl, -NR 5 ' - (CH 2 ) m' -R 6 ' (wherein R 5' represents a hydrogen atom or methyl, R 6 'is selected from phenyl, pyridyl, or a fluorine atom-substituted phenyl) and -NR 7' -CO- (CH 2) n '-R 8' ( wherein R 7 'is a hydrogen atom, n' is 2, R 8 ' Phenyl), and more preferred examples include a chlorine atom, cyanophenyl, phenylamino and phenethylcarbonylamino. The most preferred examples include a chlorine atom and 3-cyanophenyl.
R4의 바람직한 예로서는 -(CH2)a'-CO-NH-R9'(여기서 a'는 1, R9'은 메틸, 히드록시에틸, 메톡시, 아미노페닐, 히드록시페닐, 피리딜 또는 메톡시피리딜) 및 -(CH2)b'-COOR10'(여기서 b'는 1, R10'은 메틸 또는 에틸)을 들 수 있고, 히드록시페닐아미노카르보닐메틸, 메톡시카르보닐메틸을 보다 바람직한 예로서 들 수 있다. 가장 바람직한 예로서는, 4-히드록시페닐아미노카르보닐메틸 및 메톡시카르보닐메틸을 들 수 있다. 또한, R4이 결합되어 있는 탄소 원자는 비대칭 탄소 원자이고, 그 입체 배치는 S배치, R배치 및 이들 혼합물 중 어느 것이어도 좋지만, S배치인 것이 바람직하다. Preferred examples of R 4 include - (CH 2 ) a ' -CO-NH-R 9' wherein a 'is 1 and R 9' is methyl, hydroxyethyl, methoxy, aminophenyl, Methoxypyridyl) and - (CH 2 ) b ' -COOR 10' (wherein b 'is 1 and R 10' is methyl or ethyl), and hydroxyphenylaminocarbonylmethyl, methoxycarbonylmethyl As a more preferable example. The most preferred examples include 4-hydroxyphenylaminocarbonylmethyl and methoxycarbonylmethyl. The carbon atom to which R 4 is bonded is an asymmetric carbon atom, and the stereostructure thereof may be S configuration, R configuration, or a mixture thereof, but it is preferable that the configuration is S configuration.
일반식 (I)로 표시되는 화합물의 바람직한 예로서는, Preferable examples of the compound represented by the general formula (I)
(S)-2-[4-(4-클로로페닐)-2,3,9-트리메틸-6H-티에노[3,2-f][1,2,4]트리아졸로[4,3-a][1,4]디아제핀-6-일]-N-(4-히드록시페닐)아세트아미드 및 그 2수화물(실시예중 화합물 1), (S) -2- [4- (4-chlorophenyl) -2,3,9-trimethyl-6H-thieno [3,2- f] [1,2,4] triazolo [ ] [1,4] diazepin-6-yl] -N- (4-hydroxyphenyl) acetamide and its dihydrate (Compound 1 in the Examples)
메틸(S)-{4-(3'-시아노비페닐-4-일)-2,3,9-트리메틸-6H-티에노[3,2-f][1,2,4]트리아졸로[4,3-a][1,4]디아제핀-6-일}아세테이트(실시예중 화합물 2),Methyl (S) - {4- (3'-cyanobiphenyl-4-yl) -2,3,9-trimethyl-6H- thieno [3,2- f] [1,2,4] triazolo [ 4,3-a] [1,4] diazepin-6-yl} acetate (compound 2 in the examples)
메틸(S)-{2,3,9-트리메틸-4-(4-페닐아미노페닐)-6H-티에노[3,2-f][1,2,4]트리아졸로[4,3-a][1,4]디아제핀-6-일}아세테이트(실시예중 화합물 8), 및 Methyl (S) - {2,3,9-trimethyl-4- (4-phenylaminophenyl) -6H-thieno [3,2- f] [1,2,4] triazolo [ ] [1,4] diazepin-6-yl} acetate (Compound 8 in the Examples), and
메틸(S)-{2,3,9-트리메틸-4-[4-(3-페닐프로피오닐아미노)페닐]-6H-티에노[3,2-f][1,2,4]트리아졸로[4,3-a][1,4]디아제핀-6-일}아세테이트(실시예중 화합물 10)을 들 수 있고, Methyl (S) - {2,3,9-trimethyl-4- [4- (3- phenylpropionylamino) phenyl] -6H- thieno [3,2- f] [1,2,4] [4,3-a] [1,4] diazepin-6-yl} acetate (compound 10 in the examples)
(S)-2-[4-(4-클로로페닐)-2,3,9-트리메틸-6H-티에노[3,2-f][1,2,4]트리아졸로[4,3-a][1,4]디아제핀-6-일]-N-(4-히드록시페닐)아세트아미드 및 그 2수화물을 보다 바람직한 예로서 들 수 있다. (S) -2- [4- (4-chlorophenyl) -2,3,9-trimethyl-6H-thieno [3,2- f] [1,2,4] triazolo [ ] [1,4] diazepin-6-yl] -N- (4-hydroxyphenyl) acetamide and its dihydrate are more preferred examples.
본 발명에 있어서 유효 성분으로서 이용할 수 있는 화합물은 유리(遊離) 형태의 화합물 외에, 의약상 허용할 수 있는 염을 이용하여도 좋다. 의약상 허용할 수 있는 염으로서는, 염산, 황산, 브롬화수소염, 인산 등의 무기산과의 염; 메탄술폰산, p-톨루엔술폰산, 아세트산, 옥살산, 시트르산, 말산, 푸마르산 등의 유기산과의 염; 나트륨, 칼륨 등의 알칼리 금속과의 염; 마그네슘 등의 알칼리 토류 금속과의 염; 암모니아, 에탄올아민, 2-아미노-2-메틸-1-프로판올 등의 아민과의 염을 들 수 있다. 이 외, 의약으로서 허용되는 것이면 염의 종류는 특별히 한정되지는 않는다.The compound usable as the active ingredient in the present invention may be a pharmaceutically acceptable salt in addition to the free (free) form compound. Pharmaceutically acceptable salts include salts with inorganic acids such as hydrochloric acid, sulfuric acid, hydrogen bromide, and phosphoric acid; Salts with organic acids such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, oxalic acid, citric acid, malic acid and fumaric acid; Salts with alkali metals such as sodium and potassium; Salts with alkaline earth metals such as magnesium; Ammonia, ethanolamine, and salts with amines such as 2-amino-2-methyl-1-propanol. In addition, the type of salt is not particularly limited as long as it is acceptable as a medicament.
또한, 본 발명에서 유효 성분으로서 이용할 수 있는 화합물은, 용매화물로서 이용하여도 좋다. 용매화물로서는, 에탄올아세트산에틸 등과의 용매화물을 들 수 있다. 이 외, 의약으로서 허용되는 것이면, 용매화물의 종류는 특별히 한정되지는 않는다. The compound that can be used as an active ingredient in the present invention may be used as a solvate. As the solvate, there can be mentioned a solvate with ethyl acetate, ethyl acetate or the like. In addition, the type of the solvate is not particularly limited as long as it is acceptable as a medicament.
식 (I)로 표시되는 화합물은 모두 공지의 화합물이고, 국제 공개 팜플렛 WO98/11111호나 국제 공개 팜플렛 WO2006/129623호 공보 등에 기재된 방법에 의해 당업자가 용이하게 합성할 수 있다. The compounds represented by the formula (I) are all known compounds and can be easily synthesized by those skilled in the art by methods described in International Publication Pamphlets WO98 / 11111 and International Publication Pamphlet WO2006 / 129623.
본 발명의 유효 성분은 제약상 허용할 수 있는 담체(부형제, 결합제, 붕괴제등)와 혼합하여 얻어지는 의약 조성물 또는 제제(예컨대 정제, 액제 등)의 형태로 경구적 또는 비경구적으로 투여할 수 있다. 의약 조성물은 통상의 방법에 따라 제제화할 수 있다. The active ingredient of the present invention can be administered orally or parenterally in the form of a pharmaceutical composition or preparation (for example, tablet, liquid preparation, etc.) obtained by mixing with a pharmaceutically acceptable carrier (excipient, binder, disintegrant, etc.) . The pharmaceutical composition may be formulated according to a conventional method.
유효 성분의 투여량은 연령, 체중, 일반적 건강 상태, 성별, 식사, 투여 시간, 투여 방법, 배설 속도, 약물의 조합, 환자를 치료할 때의 병상의 정도에 따라, 이들 또는 이 외의 요인을 고려하여 정할 수 있다. 구체예를 들면, 1일 투여량은, 환자의 상태나 체중, 화합물의 종류, 투여 경로 등에 따라 상이하지만, 예컨대 경구적으로는 0.01 ㎎/㎏∼1000 ㎎/㎏ 체중/일이며, 1일 1∼수회로 나눠 투여되고, 또한 비경구적으로는 약 0.01 ㎎/㎏∼100 ㎎/㎏ 체중/일을 1일 1∼수회로 나눠 투여하는 것이 바람직하다. The dosage of the active ingredient may be determined depending on factors such as age, weight, general health, sex, diet, time of administration, administration method, excretion rate, combination of drugs, Can be determined. For example, the dosage per day is 0.01 mg / kg to 1000 mg / kg body weight per day orally, and varies depending on the condition or body weight of the patient, the kind of compound, And it is preferable to administer parenterally about 0.01 mg / kg to 100 mg / kg body weight per day in 1 to several times a day.
본 발명에 있어서 제공되는 항암제는 적응되는 암종을 불문하지만, 구체예 로서는 혈액암, 골수종, 간암, 난소암, 전립선암, 폐암, 골육종, 대장암, 유방암, 피부암, 상피성 세포암(midline carcinoma)을 들 수 있다. 이 중에서 바람직한 암종으로서는 혈액암, 골수종, 간암, 난소암, 전립선암, 폐암, 골육종, 대장암을 들 수 있고, 혈액암, 전립선암, 폐암, 대장암을 보다 바람직한 예로 들 수 있다. 본 발명에서 혈액암이란 림프종, 백혈병을 포함하는 것이다. 본 발명에서 항암제란 제암제, 항종양제 등을 포함하는 개념이고, 암을 예방 및/또는 치료할 목적으로, 암종을 축소 또는 소멸시키거나 또는 암종을 증대시키지 않는 효과를 갖는 것이다. 또한 본 발명에 있어서, 「예방」이란 질환을 발증하지 않는 건상인에 대하여 본 발명의 유효 성분을 투여하는 행위이고, 예컨대 질환의 발증을 방지하는 것을 목적으로 하는 것이다. 「치료」란 의사에 의해 질환을 발증하고 있는 것으로 진단된 사람(환자)에 대하여 본 발명의 유효 성분을 투여하는 행위이며, 예컨대 질환이나 증상을 경감하는 것, 암종을 증대시키지 않는 것 또는 질환 발증 전의 상태로 복귀시키는 것을 목적으로 하는 것이다. 또한, 투여 목적이 질환이나 증상의 악화 방지 또는 암종의 증대 방지여도, 투여받는 것이 환자이면, 치료 행위이다. Examples of the anticancer agent provided in the present invention include blood cancer, myeloma, liver cancer, ovarian cancer, prostate cancer, lung cancer, osteosarcoma, colon cancer, breast cancer, skin cancer, midline carcinoma, . Among these, preferable cancers include blood cancer, myeloma, liver cancer, ovarian cancer, prostate cancer, lung cancer, osteosarcoma, and colon cancer, and blood cancer, prostate cancer, lung cancer and colon cancer are more preferable examples. In the present invention, blood cancer includes lymphoma and leukemia. In the present invention, the term "anticancer agent" is intended to include anti-cancer agents, antitumor agents, and the like, and has an effect of reducing or eliminating carcinomas or increasing carcinomas for the purpose of preventing and / or treating cancer. In the present invention, " prevention " is an act of administering the active ingredient of the present invention to a subject who does not develop the disease, for example, to prevent the onset of the disease. The term " treatment " refers to an act of administering the active ingredient of the present invention to a person (patient) who is diagnosed as having a disease by a doctor, and includes, for example, alleviating a disease or symptom, To return to the previous state. In addition, even if the administration purpose is prevention of deterioration of the disease or symptom or prevention of the increase of the carcinoma, if the patient is a patient to be administered, it is a treatment action.
[실시예][Example]
이하에, 실시예를 이용하여 본 발명을 더 구체적으로 설명하지만, 본 발명은 이하의 실시예에 의해 한정되는 것이 아니다. Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to the following Examples.
합성예Synthetic example
이하에 나타내는 화합물 1을 WO98/11111호의 실시예 2, 화합물 2를 WO2006/129623호의 실시예 8에 기재된 방법에 준하여 작성하였다. 이 외의 화합물 3∼18에 대해서도 마찬가지로 국제 공개 팜플렛 WO98/11111호 또는 국제 공개 팜플렛 WO2006/129623호의 실시예에 기재된 방법에 준하여 합성하였다. Compound 1 shown below was prepared according to the method described in Example 8 of WO98 / 11111 and compound 2 described in Example 8 of WO2006 / 129623. The other compounds 3 to 18 were similarly synthesized in accordance with the methods described in the examples of International Publication Pamphlet WO98 / 11111 or International Publication Pamphlet WO2006 / 129623.
실시예 1 아세틸화 히스톤 H4와 BRD2, 3 및 4의 결합 저해 시험 Example 1 Binding inhibition test of acetylated histone H4 and BRD2, 3 and 4
Flag-tag을 부가한 BRD2, 3 및 4의 cDNA를 포함하는 발현 벡터를 CHO 세포에 트랜스펙트하고, 24시간 후에 세포 용해액을 조제하였다. 아세틸화 히스톤 H4와 BRD의 결합은 Time Resolved Fluorescence Resonance Energy Transfer(TR-FRET)법을 이용하여 확인하였다. 384-well white plate(Coaster사 제조)에 50 ㎚ol/L의 비오틴 표지 아세틸화 히스톤 H4 펩티드(Upstate사 제조)와 단계 희석한 피검 화합물을 가하였다. 또한 BRD 발현 벡터를 트랜스펙트한 CHO 세포 용해액, 유로피움 표지 항Flag 항체(Cisbio사 제조), 및 XL-665 표지 아비딘(Cisbio사 제조)을 가하고, 실온에서 30분 내지 2시간 반응시켰다. FRET에 의한 형광을 EnVision 2103 Multilabel Reader(Perkin Elmer사 제조)로 측정하였다. 결합 저해 활성은, 화합물 비첨가군의 카운트에 대한 화합물 첨가군의 카운트의 감소율로 나타내고, 화합물의 농도를 바꿔 구한 카운트의 감소율과 화합물의 농도를 나타낸 용량-반응 곡선으로부터 IC50값을 구하였다. An expression vector containing cDNA of BRD2, 3 and 4 to which a Flag-tag was added was transfected into CHO cells, and a cell lysate was prepared after 24 hours. The binding of acetylated histone H4 to BRD was confirmed by the Time Resolved Fluorescence Resonance Energy Transfer (TR-FRET) method. A biotin labeled acetylated histone H4 peptide (manufactured by Upstate) at 50 nmol / L and a stepwise diluted test compound were added to a 384-well white plate (Coaster). A CHO cell lysate transfected with a BRD expression vector, an europium-labeled anti-Flag antibody (manufactured by Cisbio), and XL-665 labeled avidin (manufactured by Cisbio) were added and reacted at room temperature for 30 minutes to 2 hours. Fluorescence by FRET was measured with EnVision 2103 Multilabel Reader (Perkin Elmer). The binding inhibition activity was expressed by the decreasing rate of the count of the compound addition group relative to the count of the compound non-addition group, and the IC 50 value was obtained from the dose-response curve showing the reduction rate of the count and the concentration of the compound obtained by changing the concentration of the compound.
화합물 1의 IC50(㎚ol/L)값은 아세틸화 히스톤 H4-BRD2가 55.5, 아세틸화 히스톤 H4-BRD3이 120.2, 아세틸화 히스톤 H4-BRD4가 136.1이었다. 그 외의 화합물의 IC50값을 표 2에 나타냈다. The IC 50 (nmol / L) value of Compound 1 was 55.5 for acetylated histone H4-BRD2, 120.2 for acetylated histone H4-BRD3, and 136.1 for acetylated histone H4-BRD4. The IC 50 values of the other compounds are shown in Table 2.
실시예 2 암 세포에 대한 증식 억제 활성 시험 Example 2 Test for proliferation inhibition activity on cancer cells
10% Fetal bovine serum을 포함하는 RPMI1640 배지(SIGMA사 제조)를 이용하여, 사람 전골수성 백혈병 유래 세포주 HL-60, 사람 급성 림프아구성 백혈병 유래 세포주 MOLT4, 사람 버킷 림프종 유래 세포주 Daudi, 사람 다발성 골수종 유래 세포주 RPMI-8226을 각각 37℃, 5% CO2하에서 배양하였다. 또한 10% Fetal bovine serum을 포함하는 ISKOV 배지(SIGMA사 제조)를 이용하여, 사람 만성 골수성 백혈병 유래 세포주 MV4-11을 37℃, 5% CO2하에서 배양하였다. 또한 10% Fetal bovine serum을 포함하는 DMEM/F-12 배지(SIGMA사 제조)를 이용하여, 사람 폐암 세포 유래세포주 EBC-1, 사람 간세포암 유래 세포주 Kim-1, 사람 결장암 유래 세포주 HCT-116, 사람 전립선암 유래 세포주 PC-3, 사람 난소암 유래 세포주 A2780, 사람 골육종 유래 세포주 Saos2를 각각 37℃, 5% CO2하에서 배양하였다. 이들 세포를 96 구멍 플레이트에 파종하고, 1일간 배양한 후, 거기에 배지로 희석한 화합물을 종농도 0.0003 μM∼10 μM(최종 DMSO 농도, 0.4%)이 되도록 첨가하였다. 3일간 더 배양한 후, WST-8(0.16 ㎎/mL)를 배양액에 가하여 2시간 배양하였다. 450 ㎚의 흡광도로부터 650 ㎚의 흡광도를 줄인 값을 측정하였다. 증식 억제 활성은, 화합물 비첨가군의 흡광도에 대한 화합물 첨가군의 흡광도의 감소율로 나타내고, 화합물의 농도를 바꿔 구한 흡광도의 감소율과 화합물의 농도를 나타낸 용량-반응 곡선으로부터 GI50값을 구하였다. Human leukemia-derived leukemia-derived cell line HL-60, human acute lymphoblastic leukemia-derived cell line MOLT4, human bucket lymphoma-derived cell line Daudi, and human multiple myeloma derived from RPMI1640 medium (manufactured by SIGMA) containing 10% fetal bovine serum Cell line RPMI-8226 was cultured at 37 ° C and 5% CO 2 , respectively. The human chronic myelogenous leukemia-derived cell line MV4-11 was cultured in an ISKOV medium (manufactured by SIGMA) containing 10% fetal bovine serum at 37 ° C under 5% CO 2 . Human lung cancer cell line EBC-1, human hepatocyte cancer-derived cell line Kim-1, human colon cancer-derived cell line HCT-116, and human colon cancer cell line were cultured in DMEM / F-12 medium (manufactured by SIGMA) containing 10% fetal bovine serum. Human prostate cancer-derived cell line PC-3, human ovarian cancer-derived cell line A2780 and human osteosarcoma-derived cell line Saos2 were cultured at 37 ° C and 5% CO 2 , respectively. These cells were inoculated on a 96-well plate and cultured for 1 day. Then, the compound diluted with the medium was added thereto so as to have a final concentration of 0.0003 μM to 10 μM (final DMSO concentration, 0.4%). After further culturing for 3 days, WST-8 (0.16 mg / mL) was added to the culture medium and cultured for 2 hours. The absorbance at 450 nm was subtracted from the absorbance at 650 nm. The proliferation inhibitory activity was expressed by the decrease rate of the absorbance of the compound addition group with respect to the absorbance of the compound non-addition group, and the GI 50 value was determined from the dose-response curve showing the rate of decrease of the absorbance and the concentration of the compound obtained by changing the concentration of the compound.
화합물 1 및 2의 GI50(μmol/L)값을 표 1에 나타냈다. The values of GI 50 (μmol / L) of the compounds 1 and 2 are shown in Table 1.
그 외 화합물에 대한 GI50(㎚ol/L)값을 표 2에 나타냈다.
The values of GI 50 (nmol / L) for other compounds are shown in Table 2.
이상의 결과로부터, 아세틸화 히스톤, 보다 상세하게는 아세틸화 히스톤 H4와 브로모도메인 함유 단백질, 보다 상세하게는 사람 유래의 BET 패밀리 단백질인 BRD2, BRD3, BRD4와의 결합을 저해하는 화합물은 항암제로서 이용하는 것이 가능한 것이 명백해졌다. 또한 아세틸화 히스톤과 브로모도메인 함유 단백질의 결합을 저해하는 화합물인 상기 일반식 (I)로 표시되는 티에노트리아졸로디아제핀 화합물은 항암제로서 유용한 것도 명백해졌다. 또한 상기 일반식 (I)로 표시되는 티에노트리아졸로디아제핀 화합물은 아세틸화 히스톤과 브로모도메인 함유 단백질의 결합 저해 활성을 갖고 있는 것이 명백해졌다. From the above results, a compound inhibiting the binding of acetylated histone, more specifically, acetylated histone H4 and a bromo domain-containing protein, and more specifically, a human-derived BET family protein, BRD2, BRD3 and BRD4 is used as an anticancer agent It became clear that it was possible. It has also become apparent that the thienotriazoloidazepine compound represented by the above general formula (I), which is a compound inhibiting the binding of an acetylated histone and a bromo domain-containing protein, is useful as an anticancer agent. It has also become clear that the thienotriazolyldiazepine compound represented by the above general formula (I) has a binding inhibitory activity between the acetylated histone and the bromo domain-containing protein.
본 발명에 의하면, 신규 항암제를 제공하는 것이 가능하다. According to the present invention, it is possible to provide a novel anticancer agent.
본원은, 일본에서 출원된 일본 특허 출원 2007-339456을 기초로 하고 있고, 그 내용은 본 명세서에 모두 포함되는 것이다. The present application is based on Japanese Patent Application No. 2007-339456 filed in Japan, the content of which is incorporated herein by reference in its entirety.
Claims (23)
식 중,
R1은 탄소수 1∼4의 알킬,
R2은 수소 원자; 할로겐 원자; 또는 할로겐 원자 또는 수산기로 치환되어 있어도 좋은 탄소수 1∼4의 알킬,
R3은 할로겐 원자; 할로겐 원자, 탄소수 1∼4의 알킬, 탄소수 1∼4의 알콕시 또는 시아노로 치환되어 있어도 좋은 페닐; -NR5-(CH2)m-R6(여기서, R5은 수소 원자 또는 탄소수 1∼4의 알킬, m은 0∼4의 정수, R6은 할로겐 원자로 치환되어 있어도 좋은 페닐 또는 피리딜); 또는 -NR7-CO-(CH2)n-R8(여기서 R7은 수소 원자 또는 탄소수 1∼4의 알킬, n은 0∼2의 정수, R8은 할로겐 원자로 치환되어 있어도 좋은 페닐 또는 피리딜),
R4는 -(CH2)a-CO-NH-R9(여기서 a는 1∼4의 정수, R9는 탄소수 1∼4의 알킬; 탄소수 1∼4의 히드록시알킬; 탄소수 1∼4의 알콕시; 또는 탄소수 1∼4의 알킬, 탄소수 1∼4의 알콕시, 아미노 또는 수산기로 치환되어 있어도 좋은 페닐 또는 피리딜) 또는 -(CH2)b-COOR10(여기서 b는 1∼4의 정수, R10은 탄소수 1∼4의 알킬)을 나타낸다.An anticancer agent comprising, as an active ingredient, a thienothiazolazolidinazine compound represented by the following general formula (I), a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof:
Wherein,
R 1 is alkyl having 1 to 4 carbon atoms,
R 2 is a hydrogen atom; A halogen atom; Or an alkyl having 1 to 4 carbon atoms which may be substituted with a halogen atom or a hydroxyl group,
R 3 is a halogen atom; A halogen atom, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, or phenyl optionally substituted with cyano; (Wherein R 5 is a hydrogen atom or alkyl having 1 to 4 carbon atoms, m is an integer of 0 to 4, and R 6 is phenyl or pyridyl which may be substituted with a halogen atom), -NR 5 - (CH 2 ) m -R 6 ; Or -NR 7 -CO- (CH 2 ) n -R 8 wherein R 7 is a hydrogen atom or an alkyl having 1 to 4 carbon atoms, n is an integer of 0 to 2, R 8 is phenyl or pyridyl optionally substituted with a halogen atom Dill),
R 4 is - (CH 2 ) a -CO-NH-R 9 (wherein a is an integer of 1 to 4, R 9 is alkyl having 1 to 4 carbon atoms, hydroxyalkyl having 1 to 4 carbon atoms, (CH 2 ) b -COOR 10 (wherein b is an integer of 1 to 4, preferably 1 to 4, more preferably 1 to 4, And R < 10 > represents alkyl having 1 to 4 carbon atoms).
(S)-2-[4-(4-클로로페닐)-2,3,9-트리메틸-6H-티에노[3,2-f][1,2,4]트리아졸로[4,3-a][1,4]디아제핀-6-일]-N-(4-히드록시페닐)아세트아미드 또는 그 2수화물,
메틸(S)-{4-(3'-시아노비페닐-4-일)-2,3,9-트리메틸-6H-티에노[3,2-f][1,2,4]트리아졸로[4,3-a][1,4]디아제핀-6-일}아세테이트,
메틸(S)-{2,3,9-트리메틸-4-(4-페닐아미노페닐)-6H-티에노[3,2-f][1,2,4]트리아졸로[4,3-a][1,4]디아제핀-6-일}아세테이트 또는
메틸(S)-{2,3,9-트리메틸-4-[4-(3-페닐프로피오닐아미노)페닐]-6H-티에노[3,2-f][1,2,4]트리아졸로[4,3-a][1,4]디아제핀-6-일}아세테이트인 것인 항암제. The compound according to claim 1, wherein the compound represented by formula (I)
(S) -2- [4- (4-chlorophenyl) -2,3,9-trimethyl-6H-thieno [3,2- f] [1,2,4] triazolo [ ] [1,4] diazepin-6-yl] -N- (4-hydroxyphenyl) acetamide or a dihydrate thereof,
Methyl (S) - {4- (3'-cyanobiphenyl-4-yl) -2,3,9-trimethyl-6H- thieno [3,2- f] [1,2,4] triazolo [ 4,3-a] [1,4] diazepin-6-yl} acetate,
Methyl (S) - {2,3,9-trimethyl-4- (4-phenylaminophenyl) -6H-thieno [3,2- f] [1,2,4] triazolo [ ] [L, 4] diazepin-6-yl} acetate or
Methyl (S) - {2,3,9-trimethyl-4- [4- (3- phenylpropionylamino) phenyl] -6H- thieno [3,2- f] [1,2,4] [4,3-a] [1,4] diazepin-6-yl} acetate.
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| JPJP-P-2007-339456 | 2007-12-28 |
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- 2008-12-26 KR KR1020107016835A patent/KR101600634B1/en active IP Right Grant
- 2008-12-26 JP JP2009548121A patent/JP5478262B2/en not_active Expired - Fee Related
- 2008-12-26 US US12/810,564 patent/US8476260B2/en not_active Expired - Fee Related
- 2008-12-26 CN CN2008801231078A patent/CN101910182B/en not_active Expired - Fee Related
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| JP5478262B2 (en) | 2014-04-23 |
| US20150335656A1 (en) | 2015-11-26 |
| US9125915B2 (en) | 2015-09-08 |
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| CN101910182B (en) | 2013-07-17 |
| CA2710740A1 (en) | 2009-07-09 |
| US20100286127A1 (en) | 2010-11-11 |
| CN101910182A (en) | 2010-12-08 |
| CA2710740C (en) | 2016-07-19 |
| JPWO2009084693A1 (en) | 2011-05-19 |
| WO2009084693A1 (en) | 2009-07-09 |
| KR20100112596A (en) | 2010-10-19 |
| EP2239264A1 (en) | 2010-10-13 |
| EP2239264A4 (en) | 2012-01-11 |
| US8476260B2 (en) | 2013-07-02 |
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